Combining 5-azacytidine (a demethylating drug) with a histone deacetylase (HDAC) inhibitor may prime non–small cell lung cancers (NSCLC) to better respond to immunotherapy, according to research published in Cell.1

The combination under study emerged from laboratory more than 10 years ago and has been in clinical trials ever since, said Stephen B. Baylin, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Several years ago, there was a “chance collision,” Dr Baylin said, in which his group noticed that, when 5 patients on a trial for epigenetic therapy had NSCLC progression, those treated with the first of the new checkpoint inhibitors responded. Three “did extremely well, with long-term responses and remissions.”

As the unexpected responses could be explained by immunotherapy alone or the combination with epigenetic therapy, Dr Baylin’s group has been studying this since and “went from bedside back to the lab” to determine what (if any) correlations they could find.

Immune checkpoint therapy is “a tremendous step forward, but less than half of patients with lung cancer have benefited to date,” Dr Baylin said. In their study, “the 2-drug epigenetic therapy combination worked exceedingly well in a small percentage of patients with NSCLC — even before they received the immune checkpoint inhibitor. In 2 animal models of NSCLC, the 2 agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”

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Dr Baylin, Peter Jones, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Michigan, and Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center in New York, New York — all with the Stand Up To Cancer (SU2C) team — were selected to take the concept to a clinical trial for patients with NSCLC in the inaugural SU2C Merck Catalyst Project.2

The group initiated a phase 1/1b trial to evaluate whether the HDAC inhibitor, mocetinostat, in combination with the demethylating drug, guadecitabine, can boost responses to pembrolizumab in patients with advanced NSCLC.

Dr Baylin said that “bringing in immune cells is really a key issue for checkpoint therapy; the cells have to be in the tumor to break the tolerance with immune checkpoint therapy and be effective with treatment.”